Strategic Vision and Impact on Environmental Health A. Overview Environmental genomics focuses on the study of the gene-gene and gene-environment interactions that mediate many of the complex diseases affecting human populations in today's world. This field combines the knowledge derived from modern human and molecular genetics with studies of mRNA, protein and metabolite profiling to understand how genes and genetic variations interact with environmental factors to cause disease. Integrative biology is a closely related field focused on the application of systems theory to the study of biological behavior and pathways critical to the preservation of health or the onset and progression of disease. Advances in the fields of environmental genomics and integrative biology during the past five years have been fueled by the need to translate molecular knowledge into concepts that impact our day-to-day lives and that improve the practice of environmental medicine and public health. To this end, University of Louisville (UofL) researchers have implemented academic and research programs in the areas of genetics and molecular medicine leading to the development of a strong infrastructure in DMA sequencing technologies, siRNA repositories, transcriptional profiling, mass-spectrometry (MS)-based protein analysis and proteomics, NMRand MS-based metabolomics, and more recently, bioinformatics. The establishment of a federally-funded Center for Environmental Genomics and Integrative Biology (CEGIB) at UofL will help environmental health researchers with the management and interpretation of data emerging from 'omic technologies and facilitate translation of these findings to public health and clinical practice. Full realization of the benefits offered by molecular understanding of gene, protein and metabolite expression profiles, the molecular circuitry that integrates the biological response to environmental injury, and the identification of novel biomarkers of disease, will require strong infrastructure support in the areas of bioinformatics, biostatistics, computational biology and bench-to-bedside or bench-to-community integration. In this application, we seek funding to create a National Institute of Environmental Health Sciences (NIEHS) Core Center at UofL that focuses on the application of genomics and integrative biology to problems in environmental health. The UofL Center will promote scientific achievements that advance our molecular understanding of human diseases and the role of environmental factors in the pathogenesis of disorders of cellular growth and differentiation. The thematic areas of scientific focus at UofL are environmental cardiology, environmental carcinogenesis and developmental origins of health and disease. These NIEHS-funded areas of scientific activity are ripe for continued expansion and will be greatly facilitated by the centralized infrastructure promoted by CEGIB. NIEHS investments at UofL will be leveraged by outstanding institutional commitments to continue support of core functions in transcriptional profiling, proteomics and metabolomics and to establish clinical and epidemiological research centers. Concerted efforts over the next four years will be directed at the integration of disparate datasets to identify gene, protein and metabolite networks, the development of mathematical models to simulate and predict biological behavior, and the establishment of productive partnerships between basic and clinical researchers that advance research findings in environmental genomics from the bench to the bedside. These efforts will help UofL environmental health science investigators remain competitive and at the cutting edge of biomedical research. Biological complexity is perhaps nothing more than a reflection of the complexities inherent to the natural world. If environmental health researchers are to sustain their impact in advancing the biomedical research agenda in this country, an integrated way of thinking that "marries" molecular biology to the higher levels of biological organization needs to be nurtured and cultivated among the environmental health research community. In this context, it is important to recognize that systems level thinking in environmental genomics is not restricted to biomedical questions, but that it crosses over to the domains of clinical medicine and public health. Indeed, realization of the potential of 'omic technologies will require creation of structures that support the research enterprise and advance translation of molecular findings to practice. The team of UofL researchers assembled in this application can contribute in meaningful ways to this goal.